Abstract
Conjugation of known biologically active molecules to carbohydrate frameworks represents a valuable option for the preparation of hybrid, structurally-related families of compounds with the aim of modulating their biological response. Therefore, we present here a study on the preparation of d-galacto, d-manno, d-gluco, and d-lactose glycoconjugates of an established N-hydroxyindole-based (NHI) inhibitor of lactated dehydrogenase (LDH). Structural variations involved the sugar stereochemistry and size as well as the anchoring point of the NHI on the carbohydrate frame (either C-1 or C-6). In the case of the galactose anomeric glycoconjugate (C-1), intriguing solvent-dependent effects were observed in the glycosylation stereochemical outcome. The biological activity of the deprotected glycoconjugates in contrasting lactate formation and cancer cell proliferation are described.
Highlights
Deregulation of normal cell metabolism is one of the most important hallmark of cancer cells.metabolic activities are often reprogrammed in neoplastic masses relative to healthy tissues [1].The Warburg effect, consisting of an augmented aerobic glycolysis, represents a typical case of an altered metabolic pathway in cancer [2]
In order order to to get get aa further further insight insight into into the the potential potential role role played played by by the the carbohydrate carbohydrate structure structure on on the the inhibitor inhibitor activity activity and and on on the the cellular cellular uptake uptake through through facilitative facilitative glucose glucose transporters—namely transporters—namely its its size, stereochemistry, and anchoring point, we describe a structural modulation of this class of size, stereochemistry, and anchoring point, we describe a structural modulation of this class glycoconjugate inhibitors, exemplified by and
Seven NHI glycoconjugates, which differ for the kind of sugar and for the conjugation branching point, were prepared and studied as potential lactated dehydrogenase (LDH) inhibitors
Summary
Deregulation of normal cell metabolism is one of the most important hallmark of cancer cells. The Warburg effect, consisting of an augmented aerobic glycolysis, represents a typical case of an altered metabolic pathway in cancer [2]. This effect is characterized by an increased glucose uptake and lactate production in cancer cells, regardless of hypoxic/normoxic conditions surrounding the cells. Considering that that the the high high rate rate of of glycolysis glycolysis in in cancer cells is associated with a striking glucose avidity, we set out to exploit this feature in order to cancer cells is associated with a striking glucose avidity, we set out to exploit this feature in order to improve minimize off-target off-target effects.
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